Substituted diamino-1,3,5-triazine derivatives

ABSTRACT

This invention concerns the compounds of formula  
                 
 
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R 1  and R 2  are each independently selected from hydrogen; hydroxy; amino; optionally substituted C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; Ar 1 ; mono- or di(C 1-6 alkyl)amino; mono- or di(C 1-6 alkyl)-aminocarbonyl; dihydro-2(3H)-furanone; or R 1  and R 2  taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C 1-6 alkyl)amino-C 1-4 alkylidene; R 3  is hydrogen, Ar 1 , C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxy-carbonyl, C 1-6 alkyl substituted with C 1-6 alkyloxycarbonyl; and R 4 , R 5 , R 6 , R 7  and R 8  are each independently selected from hydrogen, halo, C 1-6 alkyl, C 1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; L is optionally substituted C 1-10 alkyl; C 3-10 alkenyl; C 3-10 alkynyl; C 3-7 cycloalkyl; Ar 1  is optionally substituted phenyl; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. It further relates to new compounds being a subgroup of the compounds of formula (I), their preparation and compositions comprising them.

This application is a divisional application of prior application U.S.Ser. No. 10/397,760, filed on Mar. 26, 2003; which is a divisionalapplication of prior application U.S. Ser. No. 10/002,456, filed Nov.15, 2001, now U.S. Pat. No. 6,858,609, which is a continuation of priorapplication U.S. Ser. No. 08/938,602, filed on Sep. 26, 1997, now U.S.Pat. No. 6,380,194, which claims priority form U.S. provisionalapplication Ser. No. 60/027,260, filed Oct. 1, 1996,

The present invention is concerned with novel compounds of formula (I)having HIV replication inhibiting properties. The invention furtherrelates to methods for preparing such novel compounds, pharmaceuticalcompositions comprising said novel compounds as well as the use as amedicine of said compounds.

Compounds structurally related to the present novel compounds aredisclosed in the prior art. DE-2,121,694, published on Nov. 25, 1971,discloses a number of s-triazines useful as anti-inflammatory,tranquillising, antiviral, antispasmodic, hypo-glycaemic, diuretic, andvasodilating agents, and for modifying adreno-cortico hormone secretion.DE-2,226,474, published on Feb. 22, 1973, disclosesdiamino-1,3,5-triazine derivatives with hormone secretion-increasingactivity, and anti-inflammatory effect. Substituted triazines havingdiuretic activity were published in Guioca, Ann. Pharm. Fr., 31:283-292(1973). A number of 2,4-diamino-triazines were prepared in Kelarev V. I.et al., Khim. Geterotsikl. Soedin., 1392-1397 (1987) and Kelarev V. I.et al., Khim. Geterotsikl. Soedin., 1395-1399 (1992). The preparation of2-amino-4-benzyl-6-o-toluidino-s-triazine was described in Yuki Y. etal., Kobunshi Kagaku, 26: 141-147 (1969). The use of aralkylguanamines,in particular 2-amino-4-anilino-6-benzyl-s-triazine, for the manufactureof resins is disclosed in U.S. Pat. No. 2,817,614, granted Dec. 24,1957.

Unexpectedly, it has now been found that the compounds of formula (I)effectively inhibit the replication of the Human Immunodeficiency Virus(HIV) and consequently may be useful for the treatment of individualsinfected by HIV.

The present invention concerns the use of compounds of formula

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein

-   R¹ and R² are each independently selected from hydrogen; hydroxy;    amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;    C₁₋₆alkyloxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkyl    substituted with one or two substituents each independently selected    from amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy,    hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,    C₁₋₆alkyloxycarbonyl and thienyl; or-   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,    morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄alkylidene;-   R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with    C₁₋₆alkyloxycarbonyl; and-   R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,    hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,    amino, trihalomethyl or trihalomethyloxy;-   L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or-   L is C₁₋₁₀alkyl substituted with one or two substituents    independently selected from C₃₋₇cycloalkyl; indolyl or indolyl    substituted with one, two, three or four substituents each    independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,    amino-carbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,    C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two,    three, four or five substituents each independently selected from    halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,    amino, trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and,-   Ar¹ is phenyl, or phenyl substituted with one, two or three    substituents each independently selected from halo, C₁₋₆alkyl,    C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; for the manufacture    of a medicine for the treatment of subjects suffering from HIV    (Human Immunodeficiency Virus) infection.

This invention also concerns novel compounds of formula

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof, wherein the substituents are asdefined under formula (I); with the proviso that compounds (a) to (o)Co. No. Alk R¹/R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ a 1-(4-(2-methylpropyl)phenyl)ethylH/H H CH₃ H H H H b 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NO₂ H Hc 1-(4-(2-methylpropyl)phenyl)ethyl H/H C₆H₅ H H H H H d1-(4-(2-methylpropyl)phenyl)ethyl H/H H NO₂ H CH₃ H H e1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NH₂ H H f4-(2-methylpropyl)phenylmethyl H/H H H CF₃ H H H g1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H Cl H H h4-(2-methylpropyl)phenylmethyl H/H H H H H H H i3,4-dimethoxyphenylmethyl H/H H H H H H H j 2,3-dimethoxyphenylmethylH/H H H H H H H k 3,4-diethoxyphenylmethyl H/H H H H H H H l2-(3,5-(1,1-dimethylethyl)-4- H/H H H H H H H hydroxy-phenyl)ethyl m2-(3,5-(1,1-dimethylethyl)-4- H/H H H t-Bu OH t-Bu Hhydroxy-phenyl)ethyl n phenylmethyl H/H H CH₃ H H H H o phenylmethyl H/HH H H H H Hare not included.

The proviso is intended to exclude compounds (a) to (f) disclosed inDE-2,121,694 and DE-2,226,474; compound (g) disclosed in DE-2,226,474;compounds (h) to (k) disclosed in Guioca, Ann. Pharm. Fr., 31:283-292(1973); compounds (1) disclosed in Kelarev V. I. et al., Khim.Geterotsikl. Soedin., 1392-1397 (1987); compound (m) disclosed inKelarev V. I. et al., Khim. Geterotsikl. Soedin., 1395-1399 (1992);compound (n) disclosed in Yuki Y. et al., Kobunshi Kagaku, 26: 141-147(1969); and compound (o) disclosed in U.S. Pat. No. 2,817,614.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₂alkyl includes methyl and ethyl;C₁₋₃alkyl defines straight and branched chained saturated hydrocarbonradicals having from 1 to 3 carbon atoms such as, for example, methyl,ethyl, propyl and the like; C₁₋₄alkyl encompasses the straight andbranched chained saturated hydrocarbon radicals as defined in C₁₋₃alkylas well as the higher hdmologues thereof containing 4 carbon atoms suchas, for example; butyl and the like; C₁₋₆alkyl encompasses the straightand branched chained saturated hydro-carbon radicals as defined inC₁₋₄alkyl as well as the higher homologues thereof containing 5 or 6carbon atoms such as, for example pentyl or hexyl; C₃₋₆alkyl definesstraight and branched chained saturated hydrocarbon radicals having from3 to 6 carbon atoms such as, for example, propyl, butyl, pentyl, hexyland the like; C₂₋₆alkyl encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₃₋₆alkyl as well as ethyl;C₁₋₁₀alkyl encompasses the straight and branched chained saturatedhydrocarbon radicals as defined in C₁₋₆alkyl as well as the higherhomologues thereof containing 7 to 10 carbon atoms such as, for exampleheptyl, octyl, nonyl or decyl; C₁₋₄alkylidene defines bivalent straightand branched chained hydro-carbons having from 1 to 4 carbon atoms suchas, for example, methylene, ethylidene, propylidene, butylidene and thelike; C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl; C₃₋₁₀alkenyl defines straight and branchchained hydrocarbon radicals containing one double bond and having from3 to 10 carbon atoms such as, for example, 2-propenyl, 2-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl,2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atomattached to the triazine ring is preferably an aliphatic carbon atom;C₃₋₁₀alkynyl defines straight and branch chained hydrocarbon radicalscontaining one triple bond and having from 3 to 10 carbon atoms such as,for example, 2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl,3-methyl-2-butynyl, 3-hexynyl, 3-heptynyl, 2-octynyl, 2-nonynyl,2-decynyl and the like, whereby the carbon atom attached to the triazinering is preferably an aliphatic carbon atom; C₁₋₆alkanediyl definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the branched isomers thereof.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) or (I′) areable to form. The compounds of formula (I) or (I′) which have basicproperties can be converted in their pharmaceutically acceptable acidaddition salts by treating said base form with an appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric;nitric; phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic,malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic andthe like acids.

The term addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I) or (I′) are able toform. Examples of such forms are e.g. hydrates, alcoholates and thelike.

The term stereochemically isomeric forms of compounds of formula (I) or(I′), as used hereinbefore, defines all possible compounds made up ofthe same atoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) or (I′) may possess. Unless other-wisementioned or indicated, the chemical designation of a compoundencompasses the mixture of all possible stereochemically isomeric formswhich said compound may possess. Said mixture may contain alldiastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds offormula (I) or (I′) both in pure form or in admixture with each otherare intended to be embraced within the scope of the present invention.

Some of the compounds of formula (I) or (I′) may also exist in theirtautomeric forms. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

Whenever used hereinafter, the term “compounds of formula (I) or (I′)”is meant to include also the pharmaceutically acceptable acid additionsalts and all stereoisomeric forms.

A special group of compounds are the compounds of formula (I-P) andinclude those compounds of formula (I) or (I′) wherein

-   R¹ and R² are each independently selected from hydrogen, C₁₋₆alkyl,    Ar¹ or mono- or di(C₁₋₆alkyl)aminocarbonyl; or-   R¹ and R² taken together may form pyrrolidinyl, piperidinyl or    morpholinyl;-   R³ is hydrogen, C₁₋₆alkyl or Ar¹; and-   Ar¹ is phenyl, or phenyl substituted with 1, 2 or 3 substituents    each independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    cyano, nitro or trifluoromethyl; and-   L is a radical of formula-   wherein Alk is C₁₋₆alkanediyl;-   R^(a), R^(b), R^(c), R^(d), R^(e), R⁴, R⁵, R⁶, R⁷ and R⁸ are each    independently selected from hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    cyano, aminocarbonyl, nitro, amino, trihalomethyl or    trihalomethyloxy; or-   R^(a) and R^(b) taken together may form a bivalent radical of    formula    —CH═CH—NR⁹—  (a-1),    —NR⁹—CH═CH—  (a-2),    -   wherein R⁹ is hydrogen or C₁₋₄alkyl.

Another special group of compounds are those compounds of formula (I-P)wherefrom the compounds (a) through (O) are excluded, said compoundsbeing represented by formula (I′-P).

Interesting compounds are those compounds of formula (I′) wherein NR¹R²is other than amino.

Other interesting compounds are those compounds of formula (I′) whereinL is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L isC₁₋₁₀alkyl substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or indolyl substituted with one,two, three or four substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenyl substitutedwith one, two, three, four or five substituents each independentlyselected from halo, C₁₋₃alkyl, C₃₋₆alkyloxy, cyano, aminocarbonyl,nitro, amino, trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl.

Still other interesting compounds are those compounds of formula (I)wherein one of the following restrictions apply:

-   i) R⁴ is hydroxy, halo, C₂₋₆alkyl, C₁₋₆alkyloxy, cyano,    aminocarbonyl, amino, trihalomethyl or trihalomethyloxy; or-   ii) R⁵ is hydroxy, halo, C₁₋₃alkyl, C₁₋₆alkyloxy, cyano,    aminocarbonyl, nitro, amino, or trihalomethyloxy; or-   iii) R⁶ is C₂₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,    trihalomethyl or trihalomethyloxy; or-   iv) R⁷ is hydroxy, halo, C₁₋₃alkyl, C₁₋₆alkyloxy, cyano,    aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; or-   v) R⁸ is hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,    aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy.

Particular compounds are those compounds of formula (I) or (I′) whereinL is C₃₋₁₀alkenyl or C₁₋₂alkyl substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl; indolyl or indolylsubstituted with one, two, three or four substituents each independentlyselected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,nitro, amino, trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenylor phenyl substituted with one, two, three, four or five substituentseach independently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, amino-carbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; more in particular, wherein L is C₅₋₈alkenyl orC₁₋₂alkyl substituted with one or two substituents independentlyselected from cyclopropyl; indolyl or indolyl substituted with halo;phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl.

Also particular compounds are those compounds of formula (I) or (I′)wherein R⁴, R⁷ and R⁸ are hydrogen and R⁵ and R⁶ each independently arehydrogen, cyano, halo or aminocarbonyl; more in particular, wherein R⁴,R⁵, R⁷ and R⁸ are hydrogen and R⁶ is cyano.

Other particular compounds are those compounds of formula (I) or (I′)wherein R¹ and R² are each independently selected from hydrogen;hydroxy; amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)-aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, amino-carbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;or R¹ and R² taken together form azido or mono- ordi(C₁₋₆alkyl)aminoC₁₋₄alkylidene; more in particular wherein R¹ ishydrogen and R² is hydrogen; hydroxy; amino; C₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkylcarbonyl; C₁₋₆alkyloxy-carbonyl; Ar¹; mono- ordi(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkylsubstituted with one or two substituents each independently selectedfrom amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy,hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonyl or thienyl.

A preferred group of compounds are those compounds of formula (I) or(I′) wherein L is 2,6-dichlorophenylmethyl.

Another preferred group of compounds are those compounds of formula (I)or (I′) wherein R³ is hydrogen, R⁴, R⁵, R⁷ and R⁸ are hydrogen and R⁶ iscyano.

Yet another group of preferred compounds are those compounds of formula(I) or (I′) wherein R¹ is hydrogen and R² is hydrogen or hyroxy.

More preferred are those compounds or formula (I) or (I′) wherein L is2,6-dichloro-phenylmethyl, R³ is hydrogen, R⁴, R⁵, R⁷ and R⁸ arehydrogen and R⁶ is cyano.

Most preferred compounds are4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile;4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]-benzonitrileand the pharmaceutically acceptable acid addition salts thereof.

In general, compounds of formula (I) can be made according to themethods described in DE-2,121,694, DE-2,226,474 and Guioca, Ann. Pharm.Fr., 31:283-292 (1973).

The compounds of formula (I-a), being compounds of formula (I) whereinR¹ and R² are hydrogen, can be prepared by reacting an intermediate offormula (II) with an intermediate of formula (III) in a reaction-inertsolvent such as, e.g. N,N-dimethylformamide.

Compounds of formula (I-b), being compounds of formula (I) wherein R³ ishydrogen, can be prepared by reacting an intermediate of formula (IV)with an intermediate of formula (V) in a reaction-inert solvent such as,e.g. N,N-dimethylformamide.

Compounds of formula (I) wherein L is C₁₋₁₀alkyl substituted withindolyl or indolyl substituted with one, two, three or four substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl, said substituents being represented by (R′)_(n)whereby n is 1 to 4 and said compounds being represented by formula(I-c), may be prepared by deprotecting an intermediate of formula (VI)wherein P is a suitable protecting group such as, for example, atoluenesulfonyloxy group or the like, according to art-knowndeprotection techniques such as refluxing in a reaction-inert solvent,e.g. water, methanol or a mixture thereof, in the presence of a base,e.g. potassium carbonate or the like.

Compounds of formula (I) wherein R¹ is hydrogen, said compounds beingrepresented by formula (I-d), can be prepared by reacting anintermediate of formula (VII) wherein W¹ is a suitable leaving groupsuch as, for example, a halogen, with an amino derivative of formula(VIII) in a reaction inert solvent such as, for example, 1,4-dioxane andthe like, in the presence of a suitable base such as, for examplessodiumhydroxide, triethylamine or N,N-diisopropylethylamine or the like.

In case R² contains a hydroxy moiety, it may be convenient to performthe above reaction with a protected form of intermediate (VIII) wherebythe hydroxy moiety bears a suitable protecting group P being, forinstance, a trialkylsilyl group, and subsequently removing theprotective group according to art-known methodologies.

Compounds of formula (I) whereby R¹ and R³ are hydrogen and R² and theC₆(R⁴R⁵R⁶R⁷R⁸) moiety are identical, said compounds being represented byformula (I-e), may be prepared by reacting an intermediate of formula(IX) wherein W² is a suitable leaving group such as, for example, ahalogen or the like, with an intermediate of formula (X) in a reactioninert solvent such as, for example, 1,4-dioxane.

Compounds of formula (I) wherein R¹ and R² are other than hydrogen andare being represented by R^(1′) and R^(2′) respectively, said compoundsbeing represented by formula (I-f-1), can be prepared by reacting anintermediate of formula (XI) with an intermediate of formula (XII)wherein W³ is a suitable leaving group such as, for example, a halogen,in a reaction-inert solvent such as, for example, N,N-dimethylformamideor N,N-dimethylacetamide, and in the presence of a suitable base suchas, for example, sodium hydride or potassium carbonate.

In case intermediate (XII) is limited to W³—Ar¹ (XII-b) and R³ ishydrogen, the reaction time may be adjusted to form the disubstitutedanalogues being represented by formula (I-f-2).

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

For instance, compounds of formula (I-a) may be reacted with ananhydride of formula (XIII) wherein R is defined such that —C(═O)—R ispart of the definition of R¹ or R², according to the method described inArch. Pharm. (Waldheim) 1986, 319, 275, thus forming compounds offormula (I-g). In this reaction, the reflux time is critical; longertimes led to lower yield of the monosubstituted endproducts andincreased formation of di- and where possible, trisubstitutedendproducts.

*: only in case R³ is hydrogen

Compounds of formula (I-a) can also be reacted with a reagent of formula(XIV) in a reaction-inert solvent such as, for example,N,N-dimethylformamide, in the presence of a base such as, for example,sodium hydride.

Some of the intermediates as mentioned hereinabove are commerciallyavailable or can be prepared according to art-known procedures, whileother intermediates are deemed novel.

Intermediates of formula (II) can be prepared by reacting a cyanoderivative of formula (XV) with ammonium chloride (XVI) or a functionalderivative thereof in a reaction-inert solvent such as, for example,toluene, and in the presence of a suitable catalyst such as, forexample, trimethylaluminium.

Intermediates of formula (III) can generally be made by reactingdiphenyl N-cyano-carbonimidate of formula (XVII), which can be preparedaccording to Webb R. L. et al., J. Heterocyclic Chem., 19:1205-1206(1982), with an aniline derivative of formula (XVIII) in areaction-inert solvent such as, e.g. N,N-dimethylformamide.

Intermediates of formula (VII) can be prepared by first making aGrignard reagent of an intermediate of formula (XIX) wherein W⁴ is asuitable leaving group such as, for example, a halogen, e.g. bromine, inthe presence of magnesium in a reaction-inert solvent such as, forexample, diethyl ether, and subsequently reacting said Grignard reagentwith an intermediate of formula (XX) wherein W⁵ is a suitable leavinggroup such as, for example, a halogen, e.g. chlorine, in areaction-inert solvent such as, for example, benzene, thus forming anintermediate of formula (XXI). It may be convenient to perform the abovereaction under a inert-atmosphere such as, for instance, argon.Intermediate (XXI) may be isolated from its reaction medium, or may bein situ further reacted with an intermediate of formula (XXII) in areaction-inert solvent such as, for example, 1,4-dioxane, and in thepresence of a suitable base such as, for example, diisopropylethaneamineor the like, thus forming an intermediate of formula (VII). Theintermediates of formula (VII) are deemed novel.

Intermediates of formula (XI) can be prepared by reacting anintermediate of formula (XXIII) with an intermediate of formula (XXIV)in a reaction-inert solvent such as, for example, N,N-dimethylformamide.

Compounds of formula (I) and some of the intermediates may have one ormore stereogenic centers in their structure, present in a R or a Sconfiguration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized as a mixture of stereoisomeric forms, inparticular in the form of racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I) show antiretroviral properties, inparticular against Human Immunodeficiency Virus (HIV), which is theaetiological agent of Acquired Immune Deficiency Syndrome (AIDS) inhumans. The HIV virus preferentially infects human T-4 cells anddestroys them or changes their normal function, particularly thecoordination of the immune system. As a result, an infected patient hasan everdecreasing number of T-4 cells, which moreover behave abnormally.Hence, the immunological defense system is unable to combat infectionsand neoplasms and the HIV infected subject usually dies by opportunisticinfections such as pneumonia, or by cancers. Other conditions associatedwith HIV infection include thrombocytopaenia, Kaposi's sarcoma andinfection of the central nervous system characterized by progressivedemyelination, resulting in dementia and symptoms such as, progressivedysarthria, ataxia and disorientation. HIV infection further has alsobeen associated with peripheral neuropathy, progressive generalizedlymphadenopathy (PGL) and AIDS-related complex (ARC).

The present compounds also show activity against HIV-1 strains that haveacquired resistance to art-known non-nucleoside reverse transcriptaseinhibitors. They also have little or no binding affinity to human α-1acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I), their pharmaceutically acceptable salts and thestereochemically isomeric forms thereof, are useful in the treatment ofindividuals infected by HIV and for the prophylaxis of theseindividuals. In general, the compounds of the present invention may beuseful in the treatment of warm-blooded animals infected with viruseswhose existence is mediated by, or depends upon, the enzyme reversetranscriptase. Conditions which may be prevented or treated with thecompounds of the present invention, especially conditions associatedwith HIV and other pathogenic retroviruses, include AIDS, AIDS-relatedcomplex (ARC), progressive generalized lymphadenopathy (PGL), as well aschronic CNS diseases caused by retroviruses, such as, for example HIVmediated dementia and multiple sclerosis.

The compounds of the present invention therefore may be used asmedicines against above-mentioned conditions. Said use as a medicine ormethod of treatment comprises the systemic administration toHIV-infected subjects of an amount effective to combat the conditionsassociated with HIV and other pathogenic retroviruses, especially HIV-1.

The subject compounds may be formulated into various pharmaceuticalforms for administration purposes. Said pharmaceutical forms orcompositions are deemed novel and consequently constitute another aspectof the present invention. Also the preparation of said compositionsconstitutes a further aspect of the present invention. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, optionally in acid addition salt form, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thesepharmaceutical compositions are desirable in unitary dosage formsuitable, particularly, for administration orally, rectally,percutaneously, or by parenteral injection. For example, in preparingthe compositions in oral dosage form, any of the usual pharmaceuticalmedia may be employed such as, for example, water, glycols, oils,alcohols and the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules, and tablets. Becauseof their ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit forms, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations whichare intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such dosage unit forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, injectable solutions or suspensions and the like, andsegregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated subject and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines andare not intended to limit the scope or use of the invention to anyextent.

Also, the combination of an antiretroviral compound and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiretroviral compound, as a combined preparation forsimultaneous, separate or sequential use in anti-HIV treatment. Thedifferent drugs may be combined in a single preparation together withpharmaceutically acceptable carriers. Said other antiretroviralcompounds may be known antiretroviral compounds such as nucleosidereverse transcriptase inhibitors, e.g. zidovudine(3′-azido-3′-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI),zalcitabine (dideoxycytidine, ddC) or lamnivudine(3′-thia-2′-3′-dideoxycytidine, 3TC) and the like; non-nucleosidereverse transciptase inhibitors such as suramine, pentamidine,thymopentin, castanospermine, dextran (dextran sulfate),foscarnet-sodium (trisodium phosphono formate), nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), tacrine (tetrahydro-aminoacridine) and thelike; compounds of the TIBO(tetrahydro-imidazo[4,5,1-jk][1,4)-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitro-phenyl)amino]-2,6-dichlorobenzene-acetamide and the like;TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g.indinavir, ritanovir, saquinovir and the like; or immunomodulatingagents, e.g. levamisole and the like.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experimental Part

Hereinafter “RT” means room temperature, “DCM” means dichloromethane,“DMF” means N,N-dimethylformamide and “ACN” means acetonitrile.

A. Preparation of the Intermediates

EXAMPLE A.1

a) A mixture of 4-cyano-aniline (2.48 g) and diphenylN-cyano-carbonimidate (5.0 g) in DMF (25 ml) was stirred for 20 hours at110° C. under argon flow. Water was added and the resulting precipitatewas filtered off, to give a brownish solid. This fraction wasrecrystallized from ACN. The precipitate was filtered off and dried,yielding 1.67 g (30%) of phenyl N′-cyano-N-(4-cyanophenyl)carbamimidate(intermediate 1). In a similar way, phenylN′-cyano-N-(3-cyanophenyl)carbamimidate (intermediate 2); phenylN′-cyano-N-(4-chlorophenyl)carbamimidate (intermediate 3) and 6-phenylN′-cyano-N,N-dimethylcarbaimidate (intermediate 7) were prepared.

b) A mixture of intermediate (7) (0.01746 mol) and2,6-dichloro-benzene-ethanimidamide (0.01746 mol) in DMF (30 ml) wasstirred for 24 hours at 85° C. After cooling, the reaction mixture wasquenched with H₂O and the precipitate was filtered off and dried,yielding 5.00 g (96.0%) of6-[(2,6-dichlorophenyl)methyl]-N-2-dimethyl-1,3,5-triazine-2,4-diamine(intermediate 31).

EXAMPLE A.2

a) A mixture of NH₄Cl (2.55 g) in toluene (100 ml) was stirred andcooled in an ice bath under argon flow. Al(CH₃)₃/toluene (23.9 ml; 2.0M) was added and the resulting mixture was stirred for 1.5 hours at RT.5-Chloro-1-[(4-methylphenyl)-sulfonyl]-1H-indole-4-acetonitrile, whichcan be prepared according to Matsumoto et al., Heterocycles, 24(11),3157-3162 (1986), (3.0 g) was added and the reaction mixture was stirredfor 24 hours at 80° C. Then, the reaction mixture was poured into aslurry of 96 g of silica gel in DCM (200 ml), stirred, filtered, and thefilter cake was washed with methanol (400 ml), and evaporated to give5.35 g of white solid. The solid was dissolved in DCM, washed with 3 NNaOH, dried with potassium carbonate, filtered, and the filtrate wasevaporated, yielding 2.80 g (89%, white solid) of5-chloro-1-[(4-methylphenyl)sulfonyl]-1H-indole-4-ethanimidamide(intermediate 4).

b) A mixture of intermediate (4) (2.61 g) and intermediate (1) (1.89 g)in DMF (25 ml) was stirred for 24 hours at 65° C. under argon flow.Water was slowly added and the precipitate filtered to give 3.55 g of anoff-white solid. The solid was stirred in refluxing ACN, cooled andfiltered to give 2.54 g (66%) of white solid. A 0.30 g sample wasrecrystallized in methanol. The precipitate was filtered off and dried,yielding 0.28 g (62%, white solid) of4-[[4-amino-6-[(4-cyanophenyl)amino]-1,3,5-triazin-2-yl]methyl]-5-chloro-1-[(4-methylphenyl)sulfonyl]-1H-indole(intermediate 5).

Table 1 lists intermediates which were prepared according to theprocedure described in example A.2a. TABLE 1

Interm No. R^(a) R^(b)  8 H 3-methoxyphenyl  9 H 3-ethoxyphenyl 10 H3,5-dimethylphenyl 11 H 2,3-dimethoxyphenyl 12 H 2,5-difluorophenyl 13 H2,3,6-trifluorophenyl 14 H 3,5-dimethoxyphenyl 15 H2,3,5,6-tetramethylphenyl 16 H 3,5-(trifluoromethyl)-phenyl 17 H2-fluoro-6-(trifluoromethyl)- phenyl 18 H 3,5-difluorophenyl 19 H2-methoxy-5-(methyl- carbonyl)-phenyl 20 H CH₂—CH═C(CH₃)₂ 21 HCH═C(CH₃)₂ 22 H CH₂—CH═C(C₂H₅)₂ 23 H 2,3,6-trichlorophenyl 24

2,6-dichlorophenyl 25 H 3-(trifluoromethoxy)- phenyl 26 H2,5-dimethoxy-phenyl

EXAMPLE A.3

Iodomethane (1.76 ml) was added to 4-cyanophenyl-thiourea (5.0 g) inacetone (100 ml). The reaction mixture was stirred overnight at RT. Theprecipitate was filtered off, dried and dissolved in DCM. The organicsolution was washed with NH₃ (aq.) (excess), dried with potassiumcarbonate, filtered, and the solvent was evaporated, yielding 4.53 g(84%, white solid) of methyl N′-(4-cyanophenyl)-carbamimidothioate(intermediate 6).

EXAMPLE A.4

a) A solution of 2-(bromomethyl)-1,3-dichlorobenzene (about 10% of 0.383mol) in diethylether (240 ml) was added to magnesium (0.383 mol) indiethylether (240 ml) under argon. Once the reaction started, theremainder of 2-(bromomethyl)-1,3-dichlorobenzene in diethylether wasadded. The solution was stirred at RT for 2.5 hours and then added viacanula to a solution of 2,4,6-trichloro-1,3,5-triazine (0.319 mol) inbenzene (480 ml) while keeping the temperature below 15° C. The reactionmixture was stirred for one hour in an ice bath, then for 2 hours at RT.A solution of 4-amino-benzonitrile (0.351 mol) inN,N-diisopropylethylamine (61.0 ml) and 1,4-dioxane (500 ml) was addedand the reaction mixture was stirred at RT for 40 hours. The solvent wasevaporated. Water and ethylacetate were added. The solution was stirred,then the solid was filtered off, washed with ethylacetate and water,yielding 129.9 g of4-[[4-chloro-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-amino]benzonitrile(intermediate 27; mp. 243-244° C.).

In a similar way,4-[[4-chloro-6-[(2,4-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(intermediate 28) and4-[[4-chloro-6-[(2-chlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(intermediate 29) were prepared.

b) 2,4-dichloro-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazine(intermediate 30) was prepared according to the procedure described inexample A.4a but was stopped prior to the addition of4-aminobenzonitrile

B. Preparation of the Final Compounds

EXAMPLE B.1

a) Intermediate (1) (1.66 g) was added to a solution of2,6-dichlorobenzene-ethanimidamide (1.29 g) in DMF (13 ml). The reactionmixture was stirred for three days at RT, then for two days at 60° C.under argon flow. Water was added and the precipitate was filtered off.This fraction was refluxed in ACN (500 ml), cooled and the precipitatewas filtered off and dried, yielding 1.58 g (67%, white solid) of4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 1).

b) Compound (1) (0.00135 mol) and acetic acid anhydride (20 ml) werecombined and heated to reflux for 10 minutes. The reaction mixture wasthen removed from the oil bath and cooled to RT. The precipitate wasfiltered off, yielding 0.25 g (45%) ofN-(4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-acetamide(compound 22).

An increase of the time of reflux led to the disubstituted (compound 40)and the trisubstituted (compound 41) analogue of compound 22.

EXAMPLE B.2

Methanol (120 ml) was added to a mixture of intermediate (5) (2.35 g)and K₂CO₃ (9.19 g) in water (40 ml). The resulting reaction mixture wasstirred and refluxed for 19 hours under argon. Water (120 ml) was added,the precipitate was filtered off and purified by column chromatographyover silica gel (eluent: DCM/2-propanone 90/10). Two desired fractionswere collected and their solvent was evaporated. The first fractiongroup was slurried in ACN, cooled, filtered off and dried, yielding 0.75g (45%, white solid) of4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 8, mp. 267-268° C.). The second column fraction group yielded0.15 g of4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzamide(compound 9). After 24 hours at RT the aqueous filtrate was filtered togive 0.25 g of compound (9). The two fractions of compound 9 werecombined, dissolved in 500 ml of refluxing methanol, hot filtered, thefiltrate concentrated to 50 ml, cooled and filtered, then dried,yielding 0.25 g (14%) of4-[[4-amino-6-[(5-chloro-1H-indol-4-yl)methyl]-1,3,5-triazin-2-yl]amino]benzamide(compound 9, mp. 204-205° C.).

EXAMPLE B.3

A mixture of compound (1) (1.0 g) and sodium hydride (0.11 g), in DMF(20 ml) was stirred for 20 minutes at RT under argon flow. Then,2-isocyanato-propane (0.27 ml) was added dropwise over 30 minutes andthe reaction mixture was allowed to stir at RT overnight. The solventwas evaporated and water added. The residue was filtered, washed withwater and diethyl ether, and recrystallized from 1,4-dioxane. Theprecipitate was filtered off and dried, yielding 0.95 g (85.1%) ofN-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-N′-(1-methylethyl)-urea(compound 6, mp. 267-268° C.).

EXAMPLE B.4

A mixture of N-[amino(methylamino)methyl]-2,6-dichloro-benzeneacetamide(4.15 g) and intermediate 6 (3.05 g) in DMF (25 ml) was stirred andrefluxed for 20 hours. The solvent was evaporated, the residue dissolvedin DMF (25 ml) and heated at 80° C. for 16 hours and at 100-108° C. foranother 66 hours. The reaction mixture was cooled, quenched with water,extracted with diethyl ether, and washed with dilute NaOH, water, brine,and dried over K₂CO₃. The solvent was evaporated, and the residue waspurified by flash column chromatography, and recrystallized from2-propanol, and finally from methanol, yielding 0.78 g (12.6%) of4-[[4-[(2,6-dichlorophenyl)methyl]-6-(methyl-amino)-1,3,5-triazin-2-yl]amino]benzonitrile(compound 7, mp. 229-230° C.).

EXAMPLE B.5

a) Intermediate (27) (0.00423 mol), 2-amino-acetamide (0.00431 mol),1,4-dioxane (20 ml) and N,N-diisopropylethylamine (0.00862 mol) werecombined and stirred at RT for 16 hours under argon. The reactionmixture was quenched with H₂O and filtered. The residue was washed withH₂O, filtered and recrystallized from ACN (200 ml). The precipitate wasfiltered off and dried, yielding 0.75 g (41.4%) of[N-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]]aminoacetamide(compound 14).

b)4-[[4-[(2,6-dichlorophenyl)methyl]-6-hydrazino-1,3,5-triazin-2yl)amino]benzonitrile(compound 15) was prepared in a similar manner as described in exampleB.5a, but N,N-diisopropylethylamine was not used.

EXAMPLE B.6

a) Intermediate (27) (0.0128 mol), 1,4-dioxane (50 ml), andO-(trimethylsilyl)hydroxyl-amine, (0.134 mol) were combined under argon.The reaction mixture was stirred at RT for 20 hours. The reactionmixture was concentrated and DCM (50 ml), NaOH (1 N; 50 ml), and HCl(1N; 100 ml) were added. The solution was stirred for one hour. Theprecipitate was filtered off and recrystallized from methanol. Theprecipitate was filtered off and dried, yielding 2.96 g (59.8%) of4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrilemonohydrochloride monohydrate (compound 21).

b) Compound (21) (0.00227 mol) was stirred in ethylacetate (50 ml). Themixture was washed with NaHCO₃ (50 ml saturated solution), then washedwith brine, dried, filtered and the solvent was evaporated. The residuewas crystallized from methanol, filtered off and dried, yielding 0.60 g(70.6%) of4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile(compound 33).

EXAMPLE B.7

A mixture of intermediate (30) (0.068 mol) and 4-amino-benzonitrile(0.0420 mol) in 1,4-dioxane (100 ml) was stirred and refluxed for 16hours under argon. The hot reaction mixture was filtered, and theresulting filtrate was concentrated. The residue was dissolved in DCM(30 ml). The precipitate was filtered off and recrystallized from ACN(250 ml). After cooling to RT, the filtrate was concentrated. Theresidue was partitioned between DCM/NaOH (3 N). The resulting solutionwas dried over K₂CO₃, filtered, and the solvent was evaporated. Theresidue was recrystallized from CH₃OH. The precipitate was filtered offand dried, yielding 1.00 g (5.0%) ofN′,N-[6-[(2,6-dichlorophenyl)methyl]1,3,5-triazin-2,4-diyl]bis[4-aminobenzonitrile](compound11).

EXAMPLE B.8

a) DMF (9.0 ml) and intermediate (31) (0.00295 mol) were added to sodiumhydride (0.00354 mol) under argon. The reaction mixture was stirred for10 minutes before adding 4-fluorobenzonitrile (0.00301 mol) and washeated at 80° C. for 3.5 hours. After cooling to RT, the reactionmixture was quenched with H₂O. The precipitate was filtered off, driedand purified by flash column chromatography over silica gel (eluent:DCM). The desired fractions were collected and the solvent wasevaporated, yielding4-[4-[(2,6-dichlorophenyl)methyl]-6-(dimethylamino)-1,3,5-triazin-2-yl]amino]-enzonitrile(compound 10).

b) Intermediate (31) (0.00671 mol), dimethylacetamide (20 ml),4-fluorobenzonitrile (0.01007 mol), and K₂CO₃ (0.02685 mol) werecombined and refluxed for 4 hours under argon. The reaction mixture wasstirred and refluxed overnight and was quenched with water and extractedwith DCM. The separated organic layer was washed with brine, dried,filtered, and the solvent was evaporated. The residue was purified byflash column chromatography (eluent: DCM). The desired fractions werecollected and the solvent was evaporated. The resdiue was crystallizedfrom CH₃OH, recrystallized from ACN and finally treated with CH₃OH. Theprecipitate was filtered off and dried, yielding 0.32 g of4,4′-[[4-[(2,6-dichlorophenyl)methyl]-6-(dimethylamino)-1,3,5-triazin-2-yl]imino]bisbenzonitrile(compound 38).

EXAMPLE B.9

A solution of sodium hydride (0.00195 mol) in DMF (7 ml) was added tocompound (1) (0.00186 mol) and the resulting solution was stirred for 5minutes under argon. Then, chloroacetic acid methyl ester (0.0186 mol)was added and the reaction mixture was heated to 70° C. for 19 hours.The reaction mixture was then quenched with water and the resultingsolid was filtered off. The residue was treated with hot ACN, thenfiltered while still hot. The residue from the cooled filtrate wasrecrystallized from 1,4-dioxane. The precipitate was filtered off,yielding 0.16 g (19.4%) of methylN-(4-cyanophenyl)-N-[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]glycine(compound 39).

EXAMPLE B.10

Sodium hydride (0.00150 mol), ACN (5 ml), compound (1) (0.00135 mol) in1,4-dioxane (10 ml), and ACN (10 ml) were combined under argon. Thesolution was stirred for 1 hour. 1-chloro-3-isocyanato-propane (0.00137mol) was added. The reaction mixture was stirred for 1 hour.1-methyl-pyrrolidinone (10 ml) was added. The reaction mixture wasstirred for 16 hours. Then, the mixture was concentrated. Theconcentrate was partitioned between DCM/H₂O. The resulting solution wasfiltered, dried over K₂CO₃, filtered, concentrated and the residue wastreated with NH₃ in 1,4-dioxane (12 ml, 0.5 M) and heated under pressureat 55° C. The resulting solution was concentrated and further purifiedby flash column chromatography (eluent: DCM/CH₃OH 95/5). The purefractions were collected and the solvent was evaporated, yielding 0.12 g(18.9%) of N-[3-[[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]propyl]urea (compound 23).

EXAMPLE B.11

NaOH (0.0128 mol), 1,4-dioxane (5 ml), and guanidine (0.0128 mol) werecombined and stirred at RT for 5 minutes under argon. Then, intermediate(27) (0.00128 mol) was added and the reaction mixture was stirred at RTfor 16 hours. The reaction mixture was quenched with H₂O, and stirred.The resulting precipitate was filtered off and the residue was stirredin refluxing methanol, cooled, and filtered, yielding 0.34 g (64.3%) ofN-[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-guanidine(compound 20).

EXAMPLE B.12

A mixture of intermediate (27) (0.00256 mol) and 3-amino-1,2-propanediol(0.00563 mol) in 1,4-dioxane (10 ml) and 1-methyl-pyrrolidinone (2 ml)was stirred at RT for 48 hours under argon. The reaction mixture wasconcentrated, quenched with DCM/H₂O and stirred. The precipitate wasfiltered off, yielding 1.12 g (86.9%) of(±)-4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 26).

EXAMPLE B.13

Compound (1) (0.0016 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (21ml) were combined and stirred vigorously at ambient temperature for 8hours. The reaction mixture was filtered and the collected solid waswashed with ether (Fraction A). Additional compound was obtained byconcentration of the filtrate (Fraction B). Fractions A and B werecombined and recrystallized from ethanol, yielding 0.15 g of4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[(dimethylamino)methylene]amino]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 62).

EXAMPLE B.14

A solution of compound (13) (0.000519 mol), LiOH.H₂O (0.000571 mol),methanol (5.0 ml) and H₂O (5.0 ml) was stirred at RT for 16 hours underargon. The reaction mixture was concentrated, redissolved in H₂O,acidified with 1.0 N HCl (0.52 ml), and stirred for 3 days. Then, thesolution was filtered, an excess of 1 N HCl and CH₃OH was added to thefiltrate, and the solution was stirred for 16 hours. The resultingprecipitate was filtered off and dried, yielding 0.18 g (72.7%) ofN-[4-[(4-cyanophenyl)-amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]glycine(compound 16).

EXAMPLE B.15

A mixture of compound (32) (0.00378 mol) in NH₃ in dioxane (50 ml) washeated in a pressure vessel at 85° C. for 9 days. The solvent wasevaporated and the resulting residue was partitioned between DCM/H₂O.The organic layer was filtered, washed with ethanol and concentrated tot 25 ml and filtered, yielding 0.54 g (30.3%) of(±)-2-[[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino-4-hydroxybutanamide(compound 34).

EXAMPLE B.16

A solution of intermediate (27) in dimethylsulfoxide was treated withNaN₃ in one portion and was stirred at RT for 28 hours. The reactionmixture was poured into ice and then filtered. The precipitate waswashed with cold water and was recrystallized from ACN, yielding 0.46 gof4-[[4-azido-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 68).

Tables 2 to 5 list the compounds that were prepared according to one ofthe above Examples. TABLE 2 Co. Ex. No. No. R¹ R² R³ salt form  1 B.1a HH H  6 B.3 H C(═O)N(CH₃)₂ H  7 B.4 H CH₃ H 10 B.8a CH₃ CH₃ H 11 B.7 H

H 12 B.5a CH₂CH₃ CH₂CH₃ H 13 B.5a H CH₂C(═O)OCH₃ H 14 B.5a H CH₂C(═O)NH₂H 15 B.5b H NH₂ H 16 B14 H CH₂C(═O)OH H Co. Ex. saltform/ No. No. R¹ R²R³ stereochem. 17 B.5a H

H (S) form 18 B.5b H (CH₂)₂OH H 19 B.5b H (CH₂)₂NH₂ H 20 B11 H

H 21 B.5b H OH H HCl.H₂O B.6a 22 B.1b H C(═O)CH₃ H 23 B.10 H(CH₂)₃NHC(═O)NH₂ H 24 B.5b H (CH₂)₄OH H 25 B.5b H (CH₂)₃OH H 26 B12 HCH₂CH(OH)CH₂OH H 27 B.5b H (CH₂)₂O(CH₂)₂OH H 28 B11 H

H 29 B.5b H (CH₂)₂N(CH₃)₂ H 30 B.5b H (CH₂)₃NH₂ H 31 B.5b H(CH₂)₃N(CH₃)₂ H 32 B.5a H

H 33 B.5b H OH H B.6b 34 B15 H

H 35 B.5b H

H 36 B11 H OCH₃ H 37 B.1b H C(═O)OCH₂CH₃ H 38 B.8b CH₃ CH₃

39 B.9 H H — CH₂C(═O)OCH₃ Co. Ex. No. No. R¹ R² R³ salt form 40 B.1b HC(═O)CH₃ —C(═O)CH₃ 41 B.1b C(═O)OCH₂CH₃ C(═O)OCH₂CH₃ — C(═O)OCH₂CH₃ 42B.1b C(═O)CH₃ C(═O)CH₃ —C(═O)CH₃ 43 B.1b H C(═O)OCH₂CH₃ — C(═O)OCH₂CH₃

TABLE 3

Co. Ex. No. No. R^(a) R^(b) R^(c) R^(d) R^(e)  2 B.1a H H H H H  3 B.1aH H H H Cl 44 B.1a Cl H H Cl Cl 45 B.1a H H H OCF₃ H 46 B.1a H OCH₃ H HOCH₃ 47 B.1a H H H OCH₃ H 48 B.1a H H H OCH₂CH₃ H 49 B.1a H CH₃ H H CH₃50 B.1a H H H OCH₃ OCH₃ 51 B.1a H F H H F 52 B.1a F F H H F 53 B.1a HOCH₃ H OCH₃ H 54 B.1a CH₃ CH₃ H CH₃ CH₃ 55 B.1a H Br H H OCH₃ 56 B.1a HCF₃ H H CF₃ 57 B.1a H CH₃ H H CH₃ 58 B.1a F H H H CF₃ 59 B.1a H F H F H60 B.1a H C(═O)CH₃ H H OCH₃ 66 B.5b H H Cl H Cl 67 B.5b H H F H Cl

TABLE 4

Co. Ex. No. No. R NR¹R² R^(a) R^(c) R⁵ R⁶ salt form  4 B.1a H NH₂ Cl HCN H  5 B.1a H NH₂ Cl H H Cl 61 B.1a

NH₂ Cl H H CN HCl.C₂H₅OH 62 B13 H N═CH—N(CH₃)₂ Cl H 68 B.16 H N₃ Cl H HCN 69 B.6a H NHOH H Cl H CN 70 B.6a H NHOH H F H CN

TABLE 5

Co. No. Ex. No. L R⁶  8 B.2

—CN  9 B.2

—CONH₂ 63 (CH₂)₂CH═C(CH₃)₂ CN 64 CH₂CH═C(CH₃)₂ CN 65 (CH₂)₂CH═C(C₂H₅)₂CNC. Pharmacological Example

EXAMPLE C.1

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line,MT4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36,445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:${\frac{{\left( {OD}_{T} \right){HIV}} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\quad{expressed}\quad{in}\quad\%},$

whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inμM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). The compounds of formula (I) were shown to inhibit HIV-1effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 6hereinbelow; the numbers between brackets in the columns “IC₅₀ (μM)” and“CC₅₀ (μM)” list the number of experiments used to calculate the meanIC₅₀ and CC₅₀ values. TABLE 6 Co. No. IC₅₀ (μM) CC₅₀ (μM) SI 1 0.002(96) >100 (200) >42553 2 0.29 (10) >100 (59) >350 3 0.013 (12) 51.6 (74)3972 4 0.24 (10) 53.6 (59) 224 5 0.017 (13) 47.5 (71) 2793 6 0.380(6) >100 (30) >263 7 0.01 (11) >100 (53) >14285 8 0.3 (28) 14.4 (122)4806 9 0.066 (12) 54.4 (60) 830 10 0.17 (5) >100 (32) >602 11 >10.4 (4)6.0 (17) <1 12 8.1 (4) >20 (1) >2 13 0.11 (6) >20 (1) >178 14 0.031 (5)9.1 (1) 293 15 0.061 (7) 44.6 (6) 732 16 2.8 (9) 79.9 (6) 28 17 4.3(4) >20 (2) >4 18 0.001 (4) >20 (2) >2030 19 0.013 (3) 10.4 (1) 81020 >100 (5) 4.3 (2) <1 21 0.002 (18) 8.9 (11) 4924 22 0.014 (7) >100(7) >6993 23 0.34 (3) 36.7 (2) 106 24 0.068 (3) 36.1 (2) 529 25 0.029(3) 51.6 (2) 1773 26 0.068 (3) 59.7 (2) 883 27 0.056 (2) 46.8 (2) 837 280.003 (3) >100 (1) >37037 29 0.005 (3) 8.7 (1) 1741 30 0.04 (3) 16.5 (1)416 31 0.019 (2) 9.6 (1) 506 32 2.0 (1) 83.4 (2) 42 33 0.002 (4) 14.1(2) 6272 34 0.057 (3) 42.3 (2) 746 35 0.70 (3) 53.0 (2) 75 36 0.005 (4)40.9 (2) 8097 37 0.011 (4) 85.0 (2) 7948 38 >100 (3) >100 (11) — 390.078 (5) >20 (1) >256 40 0.002 (4) >100 (2) >41666 41 0.013 (4) 40.2(2) 3125 44 0.003 (16) >100 (63) >35087 45 0.43 (2) >100 (2) >233 460.040 (3) >100 (1) >2506 47 0.082 (6) >20 (1) >243 48 0.074 (6) >20(1) >269 49 0.091 (6) >20 (1) >220 50 0.079 (4) >20 (1) >252 51 0.031(4) >20 (1) >640 52 0.003 (4) — >220 53 0.41 (6) >20 (1) >48 54 0.005(9) 43.8 (6) 9515 55 0.052 (10) >20 (7) >384 56 >74.4 (9) >100 (7) — 570.003 (9) 36.8 (6) 11883 58 0.014 (8) 20 (6) 1418 59 0.42 (6) >100(4) >241 60 0.039 (8) 71.4 (7) 1841 61 6.9 (9) 53.4 (8) 7 62 0.002(9) >100 (7) >41666D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

EXAMPLE D.1 Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere was added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there were added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten anddissolved in 75 ml of dichloromethane. The latter solution was added tothe former and then there were added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated color suspension andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

1-17. (canceled)
 18. A method for preparing a compound of formula (I-a),

wherein R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with C₁₋₆alkyloxycarbonyl;and R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl or trihalomethyloxy; L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl;C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L is C₁₋₁₀alkyl substituted with one ortwo substituents independently selected from C₃₋₇cycloalkyl; indolyl orindolyl substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two, three,four or five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and, Ar¹ is phenyl,or phenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; with the proviso that the following compounds Co.No. Alk R¹/R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ a 1-(4-(2-methylpropyl)phenyl)ethyl H/HH CH₃ H H H H b 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NO₂ H H c1-(4-(2-methylpropyl)phenyl)ethyl H/H C₆H₅ H H H H H d1-(4-(2-methylpropyl)phenyl)ethyl H/H H NO₂ H CH₃ H H e1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NH₂ H H f4-(2-methylpropyl)phenylmethyl H/H H H CF₃ H H H g1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H Cl H H h4-(2-methylpropyl)phenylmethyl H/H H H H H H H i3,4-dimethoxyphenylmethyl H/H H H H H H H j 2,3-dimethoxyphenylmethylH/H H H H H H H k 3,4-diethoxyphenylmethyl H/H H H H H H H l2-(3,5-(1,1-dimethylethyl)-4- H/H H H H H H H hydroxy-phenyl)ethyl m2-(3,5-(1,1-dimethylethyl)-4- H/H H H t-Bu OH t-Bu Hhydroxy-phenyl)ethyl n phenylmethyl H/H H CH₃ H H H H o phenylmethyl H/HH H H H H H

are not included, comprising the step of reacting an intermediate offormula (II),

wherein L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; orL is C₁₋₁₀alkyl substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or indolyl substituted with one,two, three or four substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; with an intermediate of formula (III),

wherein R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with C₁₋₆alkyloxycarbonyl;and R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl or trihalomethyloxy; and, Ar¹ is phenyl, or phenylsubstituted with one, two or three substituents each independentlyselected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro ortrifluoromethyl; in a reaction-inert solvent.
 19. A method for preparinga compound of formula (I-b),

wherein R¹ and R² are each independently selected from hydrogen;hydroxy; amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkylsubstituted with one or two substituents each independently selectedfrom amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy,hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonyl and thienyl; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₆alkyl)aminoC₁₋₄alkylidene; R⁴, R⁵, R⁶, R⁷ and R⁸ are eachindependently selected from hydrogen, hydroxy, halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl ortrihalomethyloxy; L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl;C₃₋₇cycloalkyl; or L is C₁₋₁₀alkyl substituted with one or twosubstituents independently selected from C₃₋₇cycloalkyl; indolyl orindolyl substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two, three,four or five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and, Ar¹ is phenyl,or phenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; with the proviso that the following compounds Co.No. Alk R¹/R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ a 1-(4-(2-methylpropyl)phenyl)ethyl H/HH CH₃ H H H H b 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NO₂ H H d1-(4-(2-methylpropyl)phenyl)ethyl H/H H NO₂ H CH₃ H H e1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NH₂ H H f4-(2-methylpropyl)phenylmethyl H/H H H CF₃ H H H g1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H Cl H H h4-(2-methylpropyl)phenylmethyl H/H H H H H H H i3,4-dimethoxyphenylmethyl H/H H H H H H H j 2,3-dimethoxyphenylmethylH/H H H H H H H k 3,4-diethoxyphenylmethyl H/H H H H H H H l2-(3,5-(1,1-dimethylethyl)-4- H/H H H H H H H hydroxy-phenyl)ethyl m2-(3,5-(1,1-dimethylethyl)-4- H/H H H t-Bu OH t-Bu Hhydroxy-phenyl)ethyl n phenylmethyl H/H H CH₃ H H H H o phenylmethyl H/HH H H H H H

are not included, comprising the step of reacting an intermediate offormula (IV),

wherein R¹ and R² are each independently selected from hydrogen;hydroxy; amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkylsubstituted with one or two substituents each independently selectedfrom amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy,hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonyl and thienyl; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₆alkyl)aminoC₁₋₄alkylidene; L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl;C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L is C₁₋₁₀alkyl substituted with one ortwo substituents independently selected from C₃₋₇cycloalkyl; indolyl orindolyl substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two, three,four or five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and Ar¹ is phenyl,or phenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; with an intermediate of formula (V),

herein R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected fromhydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,nitro, amino, trihalomethyl or trihalomethyloxy; in a reaction-inertsolvent.
 20. A method for preparing a compound of formula (I-c),

wherein R¹ and R² are each independently selected from hydrogen;hydroxy; amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkylsubstituted with one or two substituents each independently selectedfrom amino, imino, aminocarbonyl, anocarbonylamino, hydroxy,hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonyl and thienyl; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₆alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, Ar¹,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and R⁴, R⁵, R⁶, R⁷ and R⁸ areeach independently selected from hydrogen, hydroxy, halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl ortrihalomethyloxy; Ar¹ is phenyl, or phenyl substituted with one, two orthree substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; wherein n is 1 to 4 andeach R′ is independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; comprising the step of deprotecting an intermediateof formula (VI),

wherein R¹ and R² are each independently selected from hydrogen;hydroxy; amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkylsubstituted with one or two substituents each independently selectedfrom amino, imino, aminocarbonyl, aminocarbonylamino, hydroxy,hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonyl and thienyl; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₆alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, Ar¹,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and R⁴, R⁵, R⁶, R⁷ and R⁸ areeach independently selected from hydrogen, hydroxy, halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl ortrihalomethyloxy; Ar¹ is phenyl, or phenyl substituted with one, two orthree substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; wherein n is 1 to 4 andeach R′ is independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; and wherein P is a suitable protective group;according to art-known deprotection techniques.
 21. A method ofpreparing a compound of formula (I-d),

wherein each R² is independently selected from hydrogen; hydroxy; amino;C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; Ar¹;mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyl substituted with C₁₋₆alkyloxycarbonyl; and R⁴, R⁵, R⁶, R⁷ andR⁸ are each independently selected from hydrogen, hydroxy, halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl or trihalomethyloxy; L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl;C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L is C₁₋₁₀alkyl substituted with one ortwo substituents independently selected from C₃₋₇cycloalkyl; indolyl orindolyl substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two, three,four or five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and, Ar¹ is phenyl,or phenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; comprising the step of reacting an intermediate offormula (VII)

wherein R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with C₁₋₆alkyloxycarbonyl;and R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl or trihalomethyloxy; L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl;C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L is C₁₋₁₀alkyl substituted with one ortwo substituents independently selected from C₃₋₇cycloalkyl; indolyl orindolyl substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two, three,four or five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and, Ar¹ is phenyl,or phenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; and wherein W¹ is a suitable leaving group; with anamino derivative of formula (VIII),

wherein each R² is independently selected from hydrogen; hydroxy; amino;C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; Ar¹;mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;in a reaction inert and in the presence of a suitable base.
 22. A methodof preparing a compound of formula (I-e),

wherein L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; orL is C₁₋₁₀alkyl substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or indolyl substituted with one,two, three or four substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; and, Ar¹ is phenyl, or phenyl substituted with one,two or three substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; comprising thestep of reacting an intermediate of formula (IX),

wherein L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; orL is C₁₋₁₀alkyl substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or indolyl substituted with one,two, three or four substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; and W² is a suitable leaving group; with anintermediate of formula (X),H₂N—Ar¹  (X) wherein Ar¹ is phenyl, or phenyl substituted with one, twoor three substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; in a reaction inertsolvent.
 23. A method of preparing a compound of formula (I-f-1)

wherein R^(1′) and R^(2′) are each independently selected from hydroxy;amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;or R^(1′) and R^(2′) taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄alkylidene R⁴, R⁵,R⁶, R⁷ and R⁸ are each independently selected from hydrogen, hydroxy,halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl or trihalomethyloxy; L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl;C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L is C₁₋₁₀alkyl substituted with one ortwo substituents independently selected from C₃₋₇cycloalkyl; indolyl orindolyl substituted with one, two, three or four substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two, three,four or five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; Ar¹ is phenyl, orphenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; comprising the step of reacting an intermediate offormula (XI)

wherein R^(1′) and R^(2′) are each independently selected from hydroxy;amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;or R^(1′) and R^(2′) taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄alkylidene; with anintermediate of formula (XII),

wherein R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected fromhydrogen, hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,nitro, amino, trihalomethyl or trihalomethyloxy and wherein W³ is asuitable leaving group; in a reaction-inert solvent and in the presenceof a suitable base.
 24. A method for preparing a compound of formula(I-f-2),

wherein R^(1′) and R^(2′) are each independently selected from hydroxy;amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁alkylcarbonyl; C₁₋₆alkyloxycarbonyl;Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;or R^(1′) and R^(2′) taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄alkylidene; L isC₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L isC₁₋₁₀alkyl substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or indolyl substituted with one,two, three or four substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; Ar¹ is phenyl, or phenyl substituted with one, two orthree substituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; comprising the step ofreacting an intermediate of formula (XI-b);

wherein R^(1′) and R^(2′) are each independently selected from hydroxy;amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;dihydro-2(3H)-furanone; C₁₋₆alkyl substituted with one or twosubstituents each independently selected from amino, imino,aminocarbonyl, aminocarbonylamino, hydroxy, hydroxyC₁₋₆alkyloxy,carboxyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonyl and thienyl;or R^(1′) and R^(2′) taken together may form pyrrolidinyl, piperidinyl,morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄alkylidene; L isC₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or L isC₁₋₁₀alkyl substituted with one or two substituents independentlyselected from C₃₋₇cycloalkyl; indolyl or indolyl substituted with one,two, three or four substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,C₁₋₆alkylcarbonyl; with an intermediate of formula (XII-b),W³—Ar¹  (XII-b) wherein W³ is a suitable leaving group and Ar¹ isphenyl, or phenyl substituted with one, two or three substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitroor trifluoromethyl; a reaction-inert solvent and in the presence of asuitable base.